Project Summary After stroke, the nervous system is unable to fully activate the musculature, which leads to cardiovascular deconditioning. These impairments limit tasks such as walking and contribute to long term disability. The purpose of this study is to examine if a non-invasive intervention, called ischemic conditioning (IC), can improve gait speed, neural activation of the paretic leg musculature, and cardiovascular fitness when combined with traditional treadmill training. Briefly, IC is a non-invasive stimulus which is triggered by using a blood pressure cuff to briefly occlude blood flow to the tissue of interest (the paretic leg) in 5-minute bouts, done a total of 5 cycles per session, making the tissue transiently ischemic. In individuals without stroke, the IC stimulus is known to increase the excitability of motor systems and improve local regulation of blood, but the positive effects of IC on motor tasks such as walking in individuals with stroke are unknown. We propose to investigate the effects of IC on walking speed and paretic leg function with three Specific Aims. In Aim 1, we will demonstrate the benefit of combined IC and treadmill training on walking speed post stroke. We will use a prospective randomized control design with three groups of individuals with chronic stroke (25 per group) for four weeks (12 total sessions) of training: IC+Treadmill Training, IC Sham+Treadmill Training, and IC only. Walking speed will be measured at baseline, after 1 session, 6 sessions, 12 sessions, and 1 month post intervention. We anticipate the largest gains in walking speed in the stroke IC+Treadmill Training group after 12 sessions. In Aim 2, we will quantify the effects of IC and treadmill training on improvements in paretic muscle activation and fatigability. Due to enhanced neural activation of the muscle, we anticipate that IC on the paretic leg will improve strength and neuromuscular fatigability. Maximal knee extensor torque generation(strength) and ability to sustain a sub-maximal force(fatigability) will be assessed in all treatment groups described in Aim 1. We expect that the largest gains in strength and task duration to occur in the stroke IC+Treadmill group after 12 sessions. Finally, in Aim 3, we will establish that IC+Treadmill Training improves endothelial function and cardiorespiratory fitness. We hypothesize that IC+Treadmill Training will result in increased flow mediated dilation in the popliteal artery of the paretic leg and the brachial artery of the non-paretic arm. Along with improvements in muscle activation, we predict the stroke IC + Treadmill training group will have an increased aerobic capacity as assessed by a graded exercise test to measure peak oxygen uptake (VO2 Peak). These studies will be the first to quantify the effects of IC, a non-invasive, easy to administer, cost-effective intervention, on walking speed, motor function and cardiorespiratory fitness in chronic stroke. The findings from this study have the potential to greatly impact neurorehabilitation strategies by demonstrating the effectiveness of IC as an adjunct on walking function post stroke. Future studies will investigate the molecular mechanisms of IC, the effects of IC on acute stroke populations, and the efficacy of IC compared with other walking adjuncts.